2.1. Hypoxic and Hyperthermic Tumor Therapy
A relatively new and novel approach to solid tumor therapy has involved the induction of tumor hypoxia following the administration of drugs that are selectively cytotoxic to hypoxic cells (Chaplin and Acker, 1987, Int. J. Rad. Oncology, Biol. Phys. 16:911-917; Brown and Koong, 1991, J. Natl. Cancer Inst. 83:178-185). The strategy typically involves the systemic administration of a hypoxic cell cytotoxin, followed by the administration of a drug that selectively reduces tumor blood flow. The reduction in tumor blood flow traps the cytotoxic agent within the tumor mass and increases its cytotoxicity via induction of hypoxia (Babbs and DeWitt, 1981, Med. Instrum. 15:367-373; Chaplin and Acker, 1987, Int. J. Rad. Oncology, Biol. Phys. 16:911-917; Jain, 1988, Cancer Res. 48:2641-2658; Dewhirst et al., 1990, Int. J. Hyperthermia 6:971-983).
Hyperthermia adjunct therapy for tumors is an area of active investigation. An improvement in achievement of elevated temperatures has been seen with reduction in tumor blood flow with vasodilators (Dewhirst, et al., 1990, Int. J. Hyperthermia 6:971-983). Acidosis of tumors also leads to substantial sensitization to heat killing (G. M. Hahn and E. C. Shiu, Int. J. Radiat. Oncol. Biol Phys., 11:159-164, 1985).
Previous efforts to reduce tumor blood flow have focused primarily on vasodilating agents such as hydralazine or nitroprusside. It has been shown that reduction of systemic blood pressure leads to a decrease in tumor blood flow while perfusion of normal tissues either increases or is unaffected. The effects of these agents on normal tissue perfusion is due to organ selectivity in the direct effect of the drugs on arteriolar or venous tone as well as systemic effects on cardiac output and arterial blood pressure. The reduction in tumor perfusion is thought to be the result of vascular collapse in tumors due to high interstitial fluid pressure and high flow resistance in the presence of lowered arterial blood pressure (Sevick and Jain, 1989, Cancer Res. 49:3506-3512). The strategy has been shown to work effectively in murine systems and in tumor bearing dogs (Dewhirst et al., 1990, Int. J. Hyperthermia 6:971-983; Prescott et al., 1990, Int. J. Hyperthermia 23:377-385), but is directly related to the drop in blood pressure. However, the blood pressure decrease required to observe reduced tumor perfusion, to about 60% of normal blood pressure, makes the approach relatively infeasible for clinical application. Such a decrease in blood pressure is especially dangerous for elderly or weak patients. The degree of reduction in systemic blood pressure that is safe in patients is not enough to see an appreciable drop in tumor blood flow.